Parkinson's disease: symptoms and medications at the end of life.

OBJECTIVES: People with Parkinson's disease (PwP) have a high palliative symptom burden throughout their disease course, equivalent to advanced malignancy. We aim to establish trends in symptom frequency and prescribing in the 72 hours prior to death for PwP. METHODS: Retrospective case note review of PwP who died between February 2019 and September 2020. RESULTS: 51 patients were included. 60.78% of patients (n=31) had agitation and 58.82% (n=30) had pain in the final 72 hours. Patients with cognitive impairment were 4.67 times more likely to experience agitation (p=0.035) compared with those without, with higher total midazolam doses (29.18 mg vs 11.4 mg, p=0.21). Terminal motor symptoms were recorded in three patients. 28.57% of patients received the recommended dose of rotigotine for dopaminergic therapy. CONCLUSIONS: PwP have a significant symptom burden at the end of life (EOL) with levels of terminal agitation at the higher end of those expected in the general population. There was a trend towards higher doses of sedation, rather than analgesia, in people with coexistent cognitive impairment.Terminal stiffness, despite being seldom documented in the literature, is an important although infrequent symptom.Rotigotine use at EOL remains commonplace and better understanding of its effect and dosing is required.

Computational Optimization of Irradiance and Fluence for Interstitial Photodynamic Therapy Treatment of Patients with Malignant Central Airway Obstruction.

There are no effective treatments for patients with extrinsic malignant central airway obstruction (MCAO). In a recent clinical study, we demonstrated that interstitial photodynamic therapy (I-PDT) is a safe and potentially effective treatment for patients with extrinsic MCAO. In previous preclinical studies, we reported that a minimum light irradiance and fluence should be maintained within a significant volume of the target tumor to obtain an effective PDT response. In this paper, we present a computational approach to personalized treatment planning of light delivery in I-PDT that simultaneously optimizes the delivered irradiance and fluence using finite element method (FEM) solvers of either Comsol Multiphysics® or Dosie™ for light propagation. The FEM simulations were validated with light dosimetry measurements in a solid phantom with tissue-like optical properties. The agreement between the treatment plans generated by two FEMs was tested using typical imaging data from four patients with extrinsic MCAO treated with I-PDT. The concordance correlation coefficient (CCC) and its 95% confidence interval (95% CI) were used to test the agreement between the simulation results and measurements, and between the two FEMs treatment plans. Dosie with CCC = 0.994 (95% CI, 0.953-0.996) and Comsol with CCC = 0.999 (95% CI, 0.985-0.999) showed excellent agreement with light measurements in the phantom. The CCC analysis showed very good agreement between Comsol and Dosie treatment plans for irradiance (95% CI, CCC: 0.996-0.999) and fluence (95% CI, CCC: 0.916-0.987) in using patients' data. In previous preclinical work, we demonstrated that effective I-PDT is associated with a computed light dose of ≥45 J/cm2 when the irradiance is ≥8.6 mW/cm2 (i.e., the effective rate-based light dose). In this paper, we show how to use Comsol and Dosie packages to optimize rate-based light dose, and we present Dosie's newly developed domination sub-maps method to improve the planning of the delivery of the effective rate-based light dose. We conclude that image-based treatment planning using Comsol or Dosie FEM-solvers is a valid approach to guide the light dosimetry in I-PDT of patients with MCAO.

First-In-Human Computer-Optimized Endobronchial Ultrasound-Guided Interstitial Photodynamic Therapy for Patients With Extrabronchial or Endobronchial Obstructing Malignancies.

Objective: Patients with inoperable extrabronchial or endobronchial tumors who are not candidates for curative radiotherapy have dire prognoses with no effective long-term treatment options. To reveal that our computer-optimized interstitial photodynamic therapy (I-PDT) is safe and potentially effective in the treatment of patients with inoperable extra or endobronchial malignancies inducing central airway obstructions. Methods: High-spatial resolution computer simulations were used to personalize the light dose rate and dose for each tumor. Endobronchial ultrasound with a transbronchial needle was used to place the optical fibers within the tumor according to an individualized plan. The primary and secondary end points were safety and overall survival, respectively. An exploratory end point evaluated changes in immune markers. Results: Eight patients received I-PDT with planning, and five of these received additional external beam PDT. Two additional patients received external beam PDT. The treatment was declared safe. Three of 10 patients are alive at 26.3, 12, and 8.3 months, respectively, after I-PDT. The treatments were able to deliver a prescribed light dose rate and dose to 87% to 100% and 18% to 92% of the tumor volumes, respectively. A marked increase in the proportion of monocytic myeloid-derived suppressor cells expressing programmed death-ligand 1 was measured in four of seven patients. Conclusions: Image-guided light dosimetry for I-PDT with linear endobronchial ultrasound transbronchial needle is safe and potentially beneficial in increasing overall survival of patients. I-PDT has a positive effect on the immune response including an increase in the proportion of programmed death-ligand 1-expressing monocytic myeloid-derived suppressor cells.

Interstitial Photothermal Therapy Generates Durable Treatment Responses in Neuroblastoma.

Photothermal therapy (PTT) represents a promising modality for tumor control typically using infrared light-responsive nanoparticles illuminated by a wavelength-matched external laser. However, due to the constraints of light penetration, PTT is generally restricted to superficially accessible tumors. With the goal of extending the benefits of PTT to all tumor settings, interstitial PTT (I-PTT) is evaluated by the photothermal activation of intratumorally administered Prussian blue nanoparticles with a laser fiber positioned interstitially within the tumor. This interstitial fiber, which is fitted with a terminal diffuser, distributes light within the tumor microenvironment from the "inside-out" as compared to from the "outside-in" traditionally observed during superficially administered PTT (S-PTT). I-PTT improves the heating efficiency and heat distribution within a target treatment area compared to S-PTT. Additionally, I-PTT generates increased cytotoxicity and thermal damage at equivalent thermal doses, and elicits immunogenic cell death at lower thermal doses in targeted neuroblastoma tumor cells compared to S-PTT. In vivo, I-PTT induces significantly higher long-term tumor regression, lower rates of tumor recurrence, and improved long-term survival in multiple syngeneic murine models of neuroblastoma. This study highlights the significantly enhanced therapeutic benefit of I-PTT compared to traditional S-PTT as a promising treatment modality for solid tumors.

In Vivo Models for Studying Interstitial Photodynamic Therapy of Locally Advanced Cancer.

Interstitial photodynamic therapy (I-PDT) is a promising therapy considered for patients with locally advanced cancer. In I-PDT, laser fibers are inserted into the tumor for effective illumination and activation of the photosensitizer in a large tumor. The intratumoral light irradiance and fluence are critical parameters that affect the response to I-PDT. In vivo animal models are required to conduct light dose studies, to define optimal irradiance and fluence for I-PDT. Here we describe two animal models with locally advanced tumors that can be used to evaluate the response to I-PDT. One model is the C3H mouse bearing large subcutaneous SCCVII carcinoma (400-600 mm3). Using this murine model, multiple light regimens with one or two optical fibers with cylindrical diffuser ends (cylindrical diffuser fiber, CDF) can be used to study tumor response to I-PDT. However, tissue heating may occur when 630 nm therapeutic light is delivered through CDF at an intensity ≥60 mW/cm and energy ≥100 J/cm. These thermal effects can impact tumor response while treating locally advanced mice tumors. Magnetic resonance imaging and thermometry can be used to study these thermal effects. A larger animal model, New Zealand White rabbit with VX2 carcinoma (~5000 mm3) implanted in either the sternomastoid (neck implantation model) or the biceps femoris muscle (thigh implantation model), can be used to study I-PDT with image-based pretreatment planning using computed tomography. In the VX2 model, the light delivery can include the use of multiple laser fibers to test light dosimetry and delivery that are relevant for clinical use of I-PDT.

Calcium Phosphate Bone Void Filler Increases Threaded Suture Anchor Pullout Strength: A Biomechanical Study.

PURPOSE: To compare the response to cyclical loading and ultimate pull-out strength of threaded suture anchor with and without calcium phosphate bone void filler augmentation in a polyurethane foam block model and in vitro proximal humerus cadaveric model. METHODS: This controlled biomechanical study consisted of 2 parts: (1) preliminary polyurethane foam block model, and (2) in vitro cadaveric humeri model. The preliminary foam block model intended to mimic osteoporotic bone using a 0.12 g/mL foam material. Half of the foam block models were first filled with injectable calcium phosphate bone substitute material (CP-BSM), whereas the other half were not augmented with CP-BSM. Each specimen was then instrumented with a threaded suture anchor. The same technique and process was performed in a matched cadaveric humeri model. Testing then consisted of a stepwise, increasing axial load protocol for a total of 40 cycles. If the anchor remained intact after cyclic loading, the repair was loaded to failure. The number of completed cycles, failure load, and failure modes were compared between groups. RESULTS: Average pull-out strength for suture anchor with CP-BSM in the osteoporotic foam block model was significantly higher at 332.68 N ± 47.61 compared with the average pull-out strength of suture anchor without CP-BSM at 144.38 N ± 14.58 (P = .005). In the matched cadaveric humeri model, average pull-out strength for suture anchor with CP-BSM was significantly higher at 274.07 N ± 102.07 compared with the average pull-out strength of suture anchor without CP-BSM at 138.53 N ± 109.87 (P = .029). CONCLUSIONS: In this time zero, biomechanical study, augmentation of osteoporotic foam block and cadaveric bone with calcium phosphate bone substitute material significantly increases pull-out strength of threaded suture anchors. CLINICAL RELEVANCE: Considering concerns about suture anchor pull-out from osteoporotic bone, augmentation with calcium phosphate bone substitute material increases load to failure resistance.

Irradiance, Photofrin® Dose and Initial Tumor Volume are Key Predictors of Response to Interstitial Photodynamic Therapy of Locally Advanced Cancers in Translational Models.

The objective of the present study was to develop a predictive model for Photofrin® -mediated interstitial photodynamic therapy (I-PDT) of locally advanced tumors. Our finite element method was used to simulate 630-nm intratumoral irradiance and fluence for C3H mice and New Zealand White rabbits bearing large squamous cell carcinomas. Animals were treated with light only or I-PDT using the same light settings. I-PDT was administered with Photofrin® at 5.0 or 6.6 mg kg-1 , 24 h drug-light interval. The simulated threshold fluence was fixed at 45 J cm-2 while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm-2 . However, 20-90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm-2 . In the rabbits treated with I-PDT, 13 of the 14 VX2 tumors showed either local control or were cured when threshold irradiances were ≥15.3 mW cm-2 and fluence was 45 J cm-2 . No tumor growth delay was observed in VX2 treated with light only (n = 3). In the mouse studies, there was a high probability (92.7%) of predicting cure when the initial tumor volume was below the median (493.9 mm3 ) and I-PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm-2 .

An Optical Surface Applicator for Intraoperative Photodynamic Therapy.

BACKGROUND AND OBJECTIVES: Intraoperative photodynamic therapy (IO-PDT) is typically administered by a handheld light source. This can result in uncontrolled distribution of light irradiance that impacts tissue and tumor response to photodynamic therapy. The objective of this work was to characterize a novel optical surface applicator (OSA) designed to administer controlled light irradiance in IO-PDT. STUDY DESIGN/MATERIALS AND METHODS: An OSA was constructed from a flexible silicone mesh applicator with multiple cylindrically diffusing optical fibers (CDF) placed into channels of the silicone. Light irradiance distribution, at 665 nm, was evaluated on the OSA surface and after passage through solid tissue-mimicking optical phantoms by measurements from a multi-channel dosimetry system. As a proof of concept, the light administration of the OSA was tested in a pilot study by conducting a feasibility and performance test with 665-nm laser light to activate 2-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) in the thoracic cavity of adult swine. RESULTS: At the OSA surface, the irradiance distribution was non-uniform, ranging from 128 to 346 mW/cm2 . However, in the tissue-mimicking phantoms, beam uniformity improved markedly, with irradiance ranges of 39-153, 33-87, and 12-28 mW/cm2 measured at phantom thicknesses of 3, 5, and 10 mm, respectively. The OSA safely delivered the prescribed light dose to the thoracic cavities of four swine. CONCLUSIONS: The OSA can provide predictable light irradiances for administering a well-defined and potentially effective therapeutic light in IO-PDT. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer.

BACKGROUND: Currently delivered light dose (J/cm2) is the principal parameter guiding interstitial photodynamic therapy (I-PDT) of refractory locally advanced cancer. The aim of this study was to investigate the impact of light dose rate (irradiance, mW/cm2) and associated heating on tumour response and cure. METHODS: Finite-element modeling was used to compute intratumoural irradiance and dose to guide Photofrin® I-PDT in locally advanced SCCVII in C3H mice and large VX2 neck tumours in New Zealand White rabbits. Light-induced tissue heating in mice was studied with real-time magnetic resonance thermometry. RESULTS: In the mouse model, cure rates of 70-90% were obtained with I-PDT using 8.4-245 mW/cm2 and ≥45 J/cm2 in 100% of the SCCVII tumour. Increasing irradiance was associated with increase in tissue heating. I-PDT with Photofrin® resulted in significantly (p < 0.05) higher cure rate compared to light delivery alone at same irradiance and light dose. Local control and/or cures of VX2 were obtained using I-PDT with 16.5-398 mW/cm2 and ≥45 J/cm2 in 100% of the tumour. CONCLUSION: In Photofrin®-mediated I-PDT, a selected range of irradiance prompts effective photoreaction with tissue heating in the treatment of locally advanced mouse tumour. These irradiances were translated for effective local control of large VX2 tumours.

Reconstruction of a Deformed Tumor Based on Fiducial Marker Registration: A Computational Feasibility Study.

Interstitial photodynamic therapy has shown promising results in the treatment of locally advanced head and neck cancer. In this therapy, systemic administration of a light-sensitive drug is followed by insertion of multiple laser fibers to illuminate the tumor and its margins. Image-based pretreatment planning is employed in order to deliver a sufficient light dose to the complex locally advanced head-and-neck cancer anatomy, in order to meet clinical requirements. Unfortunately, the tumor may deform between pretreatment imaging for the purpose of planning and intraoperative imaging when the plan is executed. Tumor deformation may result from the mechanical forces applied by the light fibers and variation of the patient's posture. Pretreatment planning is frequently done with the assistance of computed tomography or magnetic resonance imaging in an outpatient suite, while treatment monitoring and control typically uses ultrasound imaging due to considerations of costs and availability in the operation room. This article presents a computational method designed to bridge the gap between the 2 imaging events by taking a tumor geometry, reconstructed during preplanning, and by following the displacement of fiducial markers, which are initially placed during the preplanning procedure. The deformed tumor shape is predicted by solving an inverse problem, seeking for the forces that would have resulted in the corresponding fiducial marker displacements. The computational method is studied on spheres of variable sizes and demonstrated on computed tomography reconstructed locally advanced head and neck cancer model. Results of this study demonstrate an average error of less than 1 mm in predicting the deformed tumor shape, where 1 mm is typically the order of uncertainty in distance measurements using magnetic resonance imaging or computed tomography imaging and high-quality ultrasound imaging. This study further demonstrates that the deformed shape can be calculated in a few seconds, making the proposed method clinically relevant.

Quantum dot light emitting devices for photomedical applications.

While OLEDs have struggled to find a niche lighting application that can fully take advantage of their unique form factors as thin, flexible, lightweight and uniformly large-area luminaire, photomedical researchers have been in search of low-cost, effective illumination devices with such form factors that could facilitate widespread clinical applications of photodynamic therapy (PDT) or photobiomodulation (PBM). Although existing OLEDs with either fluorescent or phosphorescent emitters cannot achieve the required high power density at the right wavelength windows for photomedicine, the recently developed ultrabright and efficient deep red quantum dot light emitting devices (QLEDs) can nicely fit into this niche. Here, we report for the first time the in-vitro study to demonstrate that this QLED-based photomedical approach could increase cell metabolism over control systems for PBM and kill cancerous cells efficiently for PDT. The perspective of developing wavelength-specific, flexible QLEDs for two critical photomedical fields (wound repair and cancer treatment) will be presented with their potential impacts summarized. The work promises to generate flexible QLED-based light sources that could enable the widespread use and clinical acceptance of photomedical strategies including PDT and PBM.

Endobronchial ultrasound-guidance for interstitial photodynamic therapy of locally advanced lung cancer-a new interventional concept.

Recent advances in interventional pulmonology led to a significant expansion of the diagnostic and therapeutic role of endobronchial ultrasound. In this paper, we describe a new concept for using endobronchial ultrasound to guide interstitial photodynamic therapy (PDT). For this purpose, we conducted in vitro and in vivo experiments using a phantom and animal models, respectively. A new 0.5 mm optical fiber, with cylindrical diffuser end, was used to deliver the therapeutic light through the 21-gauge endobronchial ultrasound needle. The animal experiments were performed under real-time ultrasonography guidance in mice and rabbits' tumor models. Safe and effective fiber placements and tumor illumination was accomplished. In addition, computer simulation of light propagation suggests that locally advanced lung cancer tumor can be illuminated. This study demonstrates the potential feasibility of this new therapeutic modality approach, justifying further investigation in the treatment of locally advanced lung cancers.

Surface markers for guiding cylindrical diffuser fiber insertion in interstitial photodynamic therapy of head and neck cancer.

BACKGROUND AND OBJECTIVES: Image-based treatment planning can be used to compute the delivered light dose during interstitial photodynamic therapy (I-PDT) of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The objectives of this work were to evaluate the use of surface fiducial markers and flexible adhesive grids in guiding interstitial placement of laser fibers, and to quantify the impact of discrepancies in fiber location on the expected light dose volume histograms (DVHs). METHODS: Seven gel-based phantoms were made to mimic geometries of LA-HNSCC. Clinical flexible grids and fiducial markers were used to guide the insertion of optically transparent catheters, which are used to place cylindrical diffuser fibers within the phantoms. A computed tomography (CT) was used to image the markers and phantoms before and after catheter insertion and to determine the difference between the planned and actual location of the catheters. A finite element method was utilized to compute the light DVHs. Statistical analysis was employed to evaluate the accuracy of fiber placement and to investigate the correlation between the location of the fibers and the calculated DVHs. RESULTS: There was a statistically significant difference (P = 0.018) between all seven phantoms in terms of the mean displacement. There was also statistically significant correlation between DVHs and depth of insertion (P = 0.0027), but not with the lateral displacement (P = 0.3043). The maximum difference between actual and planned DVH was related to the number of fibers (P = 0.0025) and the treatment time. CONCLUSIONS: Surface markers and a flexible grid can be used to assist in the administration of a prescribed DVH within 15% of the target dose provided that the treatment fibers are placed within 1.3 cm of the planned depth of insertion in anatomies mimicking LA-HNSCC. The results suggest that the number of cylindrical diffuser fibers and treatment time can impact the delivered DVHs. Lasers Surg. Med. 49:599-608, 2017. © 2017 Wiley Periodicals, Inc.

Interstitial Photodynamic Therapy-A Focused Review.

Multiple clinical studies have shown that interstitial photodynamic therapy (I-PDT) is a promising modality in the treatment of locally-advanced cancerous tumors. However, the utilization of I-PDT has been limited to several centers. The objective of this focused review is to highlight the different approaches employed to administer I-PDT with photosensitizers that are either approved or in clinical studies for the treatment of prostate cancer, pancreatic cancer, head and neck cancer, and brain cancer. Our review suggests that I-PDT is a promising treatment in patients with large-volume or thick tumors. Image-based treatment planning and real-time dosimetry are required to optimize and further advance the utilization of I-PDT. In addition, pre- and post-imaging using computed tomography (CT) with contrast may be utilized to assess the response.

A new finite element approach for near real-time simulation of light propagation in locally advanced head and neck tumors.

BACKGROUND AND OBJECTIVES: Several clinical studies suggest that interstitial photodynamic therapy (I-PDT) may benefit patients with locally advanced head and neck cancer (LAHNC). For I-PDT, the therapeutic light is delivered through optical fibers inserted into the target tumor. The complex anatomy of the head and neck requires careful planning of fiber insertions. Often the fibers' location and tumor optical properties may vary from the original plan therefore pretreatment planning needs near real-time updating to account for any changes. The purpose of this work was to develop a finite element analysis (FEA) approach for near real-time simulation of light propagation in LAHNC. METHODS: Our previously developed FEA for modeling light propagation in skin tissue was modified to simulate light propagation from interstitial optical fibers. The modified model was validated by comparing the calculations with measurements in a phantom mimicking tumor optical properties. We investigated the impact of mesh element size and growth rate on the computation time, and defined optimal settings for the FEA. We demonstrated how the optimized FEA can be used for simulating light propagation in two cases of LAHNC amenable to I-PDT, as proof-of-concept. RESULTS: The modified FEA was in agreement with the measurements (P = 0.0271). The optimal maximum mesh size and growth rate were 0.005-0.02 m and 2-2.5 m/m, respectively. Using these settings the computation time for simulating light propagation in LAHNC was reduced from 25.9 to 3.7 minutes in one case, and 10.1 to 4 minutes in another case. There were minor differences (1.62%, 1.13%) between the radiant exposures calculated with either mesh in both cases. CONCLUSIONS: Our FEA approach can be used to model light propagation from diffused optical fibers in complex heterogeneous geometries representing LAHNC. There is a range of maximum element size (MES) and maximum element growth rate (MEGR) that can be used to minimize the computation time of the FEA to 4 minutes.